WO1991001308A1 - Derives de l'acide quinolonecarboxylique - Google Patents

Derives de l'acide quinolonecarboxylique Download PDF

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Publication number
WO1991001308A1
WO1991001308A1 PCT/JP1990/000425 JP9000425W WO9101308A1 WO 1991001308 A1 WO1991001308 A1 WO 1991001308A1 JP 9000425 W JP9000425 W JP 9000425W WO 9101308 A1 WO9101308 A1 WO 9101308A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
lower alkyl
oxoquinoline
acid
group
Prior art date
Application number
PCT/JP1990/000425
Other languages
English (en)
Japanese (ja)
Inventor
Akihiro Shibata
Hideaki Matsuda
Takemitsu Asaoka
Masaru Matsumoto
Ryuichi Kawahara
Tatsuhiko Katori
Naokata Taido
Tadayuki Kuraishi
Original Assignee
Ss Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP1189214A external-priority patent/JP2526128B2/ja
Application filed by Ss Pharmaceutical Co., Ltd. filed Critical Ss Pharmaceutical Co., Ltd.
Priority to US07/807,856 priority Critical patent/US5324735A/en
Priority to KR1019910701725A priority patent/KR920701163A/ko
Publication of WO1991001308A1 publication Critical patent/WO1991001308A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel quinolone carboxylic acid derivative or a salt thereof having an excellent antibacterial action, an antibacterial agent containing the same as an active ingredient, and an intermediate for producing the same.
  • antibacterial agents such as nalidixic acid and pyromidic acid have been known as therapeutic agents for infections caused by gram-negative bacteria.
  • synthetic antibacterial agents such as nalidixic acid and pyromidic acid have been known as therapeutic agents for infections caused by gram-negative bacteria.
  • they have the drawback of being ineffective against intractable diseases such as Pseudomonas aeruginosa infection.
  • antibacterial agents with strong antibacterial activity such as norfloxacin and off-mouth oxan, have been developed and used in clinical practice.
  • the present inventor synthesized a large number of quinoline derivatives, examined their antibacterial activity and absorption into living bodies, and found that the quinoline carboxylic acid derivative represented by the general formula (I) described below. And found that the salt thereof has excellent antibacterial activity and absorbability, and completed the present invention.
  • the present invention provides the following general formula (I):
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is a hydrogen atom or a halogen atom
  • R 4 and R 5 may together contain other heteroatoms, and may be substituted.
  • the present invention provides a quinolone carboxylic acid derivative represented by the formula (I) or a salt thereof, an antibacterial agent containing the quinolone carboxylic acid derivative as an active ingredient, and a production intermediate thereof.
  • Examples thereof include a piperazinyl group, a pyrrolidinyl group, and a morpholino group.
  • Examples of the substituent include a lower alkyl group, a hydroxy group, an amino group, and an amino lower alkyl group. .
  • the lower alkyl group usually means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a II-propyl group, and a Examples include S-D-pyr, 11-butyl, isobutyl, t-butyl, n-pentyl, and 11-hexyl. Also with halogen atoms Examples include chlorine, fluorine, bromine, and iodine atoms.
  • the salt of the compound (I) of the present invention is not particularly limited as long as it is a physiologically acceptable salt, and examples thereof include an alkali metal salt, an alkaline earth metal salt, an inorganic acid salt, and an organic acid salt. .
  • lithium metal salts, lithium salts, sodium salts, magnesium salts, and the like aluminum salt; hydrochloride, sulfate, nitrate; and inorganic acid salt.
  • organic acid salts include sulphate, fumarate, maleate, lactic acid; salts, tartrate, citrate, linate, oxalate, Examples include methansulfonate and benzenesulfonate.
  • the compound of the present invention may have an asymmetric carbon atom, but in the present invention, all optically active substances and mixtures thereof Is included.
  • the compound (I) of the present invention can be produced, for example, by the following method.
  • R I R 3 R 4 and R 5 are the same as above
  • the compound ( ⁇ ) is converted into a compound (m) by hydrogenation to form a compound (m), which is then reacted with an amine (IV) to obtain a compound (V). Then, the compound (V) is dehydrogenated and hydrolyzed.
  • the compound (I) of the present invention or a salt thereof is produced.
  • the starting compound ( ⁇ ) is produced, for example, by the method described in West German Patent DE 3,522,406.
  • compound ( ⁇ ) is reacted with the compound (VI) to form a compound ( ⁇ ), which is halogenated to obtain a compound (K), which is then reacted with an amine (IV) to obtain the compound ( ⁇ ).
  • (I-1 2) is manufactured.
  • compound (I-13) is produced by subjecting compound (I-13) to Kana-decomposition.
  • the starting compound (VI) is a known compound, for example, according to the method described in Journal of Medicinal Chemistry, 23, 1358 (1980). Manufactured.
  • reaction for obtaining (K) from the compound (3 ⁇ 4) is carried out in the same manner as in the reaction for obtaining (m) from (E) in Production Method 1.
  • reaction for producing (I-13) from the compound (I-12) is as follows:
  • the thus-obtained compound (I) of the present invention can be further converted into a salt such as an alkali metal, an alkaline earth metal, an inorganic acid, or an organic acid by a conventional method, if necessary.
  • an optically active acid is allowed to act to form a diastereoisomer, and then, by crystallization, chromatography, or the like.
  • an optically active substance can be obtained.
  • an optically active substance of a target having a desired configuration can be obtained by using an optically active raw material.
  • the dosage depends on the patient's body weight, age, sex, method of administration, physical condition, medical condition, etc.
  • the appropriate dose is 200 to 800 mg, and about 5 to 40 mg per day for parenteral administration.
  • the compound (I) of the present invention can be made into antibacterial agents in various dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by a usual method.
  • compound (I) is added to an excipient, and if necessary, a binder, a disintegrant, a lubricant, It is preferable to add tablets, granules, powders, capsules, suppositories, etc. by a conventional method after adding a coloring agent, a odor correcting agent, a bulking agent, a coating agent, a sugar coating and the like.
  • compounds (I) of the present invention can be made into antibacterial agents in various dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by a usual method.
  • compound (I) is added to an excipient, and if necessary, a binder, a disintegrant, a lub
  • (I) may be previously dissolved and dispersed in an icy carrier such as distilled water for injection. Emulsification or the like, or powder for injection may be dissolved at the time of use.
  • Administration methods for injections include intravenous administration, intraarterial administration, intraportal administration, intraperitoneal administration, intramuscular administration, and subcutaneous administration.
  • the reaction product is filtered, the filtrate is concentrated under reduced pressure, 50 ml of acetic acid and 10 ml of water are added to the residue, and the mixture is hydrolyzed at 60 for 2 hours.
  • the reaction product is filtered, the filtrate is concentrated under reduced pressure, and the residue is extracted with a filter form, and the form is distilled off to obtain a residue.
  • 1-Fluoro-1,4-dihydro-1-11 (1-hydroxyprop-1-yl) 1-4-oxoquinoline 1-3-Ethylester is obtained. Melting point 2 3 8 to 2 3 9 * (:
  • the bacteria shown in Table 4 were measured under the following conditions according to the Japanese Society of Chemotherapy MIC measurement method. In addition, off- ⁇ -xascin was used as a control. The results are shown in Table 4.
  • Sample dilution Adjust to 1000 nicg Az with 25% dimethyl sulfoxide, and then dilute twice with sterile purified ice to make 100 meg to 0.006 mcg. Thereafter, dilute it 10 times with the medium to make a plate.
  • Test strain (MIC value: mgZ) Test strain
  • Bacillus subti 1 is ATCC 6633 0.049 0.098 Bug I 2.
  • Streptococcus faecal is IFO 12964 0.78 1.56
  • Table 4 shows that the compound of the present invention has a stronger antibacterial activity than ofloxacin and is useful as an antibacterial agent.
  • the compound (I) of the present invention has high antibacterial activity, high absorption and high bioavailability. is there.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Dérivés de l'acide quinolonecarboxylique selon la formule générale (I), possédant une excellente action antibactérienne, leurs sels, agents antibactériens les contenant en tant qu'ingrédient actif, et produits intermédiaires de ces dérivés selon la formule générale (V). Dans la formule (I), R1 représente alkyle inférieur, R2 représente hydrogène ou alkyle inférieur, R3 représente hydrogène ou halogène, et R4 et R5 se combinent entre eux pour former un anneau éventuellement substitué comportant 5 ou 6 éléments et pouvant contenir un ou plusieurs autres hétéroatomes, à condition que l'on exclue le cas où R1 représente méthyle, R2 et R3 représentent chacun hydrogène, et (a) est pipérazinyle. Dans la formule (V), R1 représente alkyle inférieur, R2-1 représente alkyle inférieur, R3 représente hydrogène ou halogène, X représente halogène, et R4 et R5 se combinent entre eux pour former un anneau éventuellement substitué comportant 5 ou 6 éléments et pouvant contenir un ou plusieurs autres hétéroatomes.
PCT/JP1990/000425 1988-08-08 1990-03-29 Derives de l'acide quinolonecarboxylique WO1991001308A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US07/807,856 US5324735A (en) 1989-07-21 1990-03-29 Quinoline carboxylic acid derivatives
KR1019910701725A KR920701163A (ko) 1988-08-08 1990-03-29 퀴놀론 카르복실산 유도체

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1189214A JP2526128B2 (ja) 1988-08-08 1989-07-21 キノロンカルボン酸誘導体
JP1/189214 1989-07-21

Publications (1)

Publication Number Publication Date
WO1991001308A1 true WO1991001308A1 (fr) 1991-02-07

Family

ID=16237464

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1990/000425 WO1991001308A1 (fr) 1988-08-08 1990-03-29 Derives de l'acide quinolonecarboxylique

Country Status (4)

Country Link
US (1) US5324735A (fr)
EP (1) EP0486687A4 (fr)
CA (1) CA2058424A1 (fr)
WO (1) WO1991001308A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2613139B2 (ja) * 1990-07-19 1997-05-21 エスエス製薬 株式会社 キノロンカルボン酸誘導体
WO2005026165A1 (fr) * 2003-09-12 2005-03-24 Warner-Lambert Company Llc Agents antibacteriens a base de quinolone
US7563805B2 (en) * 2005-05-19 2009-07-21 Daiichi Pharmaceutical Co., Ltd. Tri-, tetra-substituted-3-aminopyrrolidine derivative

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50106974A (fr) * 1974-01-30 1975-08-22
JPS50108276A (fr) * 1974-02-07 1975-08-26
JPS61189281A (ja) * 1985-02-15 1986-08-22 Dainippon Pharmaceut Co Ltd ピリドンカルボン酸誘導体、そのエステルおよびその塩
JPS62207258A (ja) * 1986-03-06 1987-09-11 Toyama Chem Co Ltd 新規なキノリン誘導体およびその塩
JPS63179856A (ja) * 1987-01-21 1988-07-23 Kyorin Pharmaceut Co Ltd キノロンカルボン酸誘導体の製造方法並びにその中間体
JPS63280068A (ja) * 1987-04-24 1988-11-17 バイエル・アクチエンゲゼルシヤフト キノロンカルボン酸溶液
JPH0628964A (ja) * 1991-10-15 1994-02-04 Merlin Gerin 単極ユニットを備えた多極遮断器
JPH06230776A (ja) * 1992-12-30 1994-08-19 Hyundai Electron Ind Co Ltd ディジタルオーディオ用反復再生システム
JPH06345261A (ja) * 1993-04-16 1994-12-20 Daihen Corp 自動搬送装置の搬送用ハンド

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1175836A (fr) * 1977-09-20 1984-10-09 Marcel Pesson Production de derives de l'acide 1,4- dihydroquinoline-3-carboxylique
JPS5466686A (en) * 1977-09-20 1979-05-29 Dainippon Pharmaceut Co Ltd Quinoline-3-carboxylic acid derivative, its preparation, and pharmaceutical composition containig the same
JPS5845426B2 (ja) * 1978-09-29 1983-10-08 杏林製薬株式会社 置換キノリンカルボン酸誘導体
JPS5630964A (en) * 1979-08-22 1981-03-28 Kyorin Pharmaceut Co Ltd Novel substituted quinolinecarboxylic acid and its preparation
JPS59128383A (ja) * 1982-12-29 1984-07-24 Kanebo Ltd 新規キノリンカルボン酸誘導体および該化合物を有効成分とする抗菌剤
JPS6028964A (ja) * 1983-07-28 1985-02-14 Hokuriku Seiyaku Co Ltd ７−ピペラジン又はホモピペラジン置換−１−イソプロピル−６−フルオロ−４−オキソ−１，４−ジヒドロキノリン−３−カルボン酸誘導体
FR2574404B1 (fr) * 1984-12-12 1987-04-24 Provesan Sa Derives 1-substitues de l'acide 6-fluoro-7-(pyrrol-1-yl)-1,4-dihydro-4-oxoquinoleine-3-carboxylique, leur preparation et leur application en tant que medicaments
JPH0674260B2 (ja) * 1985-08-01 1994-09-21 大日本製薬株式会社 キノリン誘導体、そのエステルおよびその塩
JPS62215572A (ja) * 1986-03-17 1987-09-22 Kyorin Pharmaceut Co Ltd キノロンカルボン酸誘導体
EP0242789A3 (fr) * 1986-04-25 1990-09-05 Dainippon Pharmaceutical Co., Ltd. Dérivés de quinoléine et procédés pour leur préparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS50106974A (fr) * 1974-01-30 1975-08-22
JPS50108276A (fr) * 1974-02-07 1975-08-26
JPS61189281A (ja) * 1985-02-15 1986-08-22 Dainippon Pharmaceut Co Ltd ピリドンカルボン酸誘導体、そのエステルおよびその塩
JPS62207258A (ja) * 1986-03-06 1987-09-11 Toyama Chem Co Ltd 新規なキノリン誘導体およびその塩
JPS63179856A (ja) * 1987-01-21 1988-07-23 Kyorin Pharmaceut Co Ltd キノロンカルボン酸誘導体の製造方法並びにその中間体
JPS63280068A (ja) * 1987-04-24 1988-11-17 バイエル・アクチエンゲゼルシヤフト キノロンカルボン酸溶液
JPH0628964A (ja) * 1991-10-15 1994-02-04 Merlin Gerin 単極ユニットを備えた多極遮断器
JPH06230776A (ja) * 1992-12-30 1994-08-19 Hyundai Electron Ind Co Ltd ディジタルオーディオ用反復再生システム
JPH06345261A (ja) * 1993-04-16 1994-12-20 Daihen Corp 自動搬送装置の搬送用ハンド

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0486687A4 *

Also Published As

Publication number Publication date
US5324735A (en) 1994-06-28
EP0486687A4 (en) 1992-06-17
CA2058424A1 (fr) 1991-01-22
EP0486687A1 (fr) 1992-05-27

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